Methods and compositions for inhibiting c-met dimerization and activation

Abstract

The invention provides methods and compositions for modulating the HGF/c-met signaling pathway, in particular by regulating c-met dimerization and/or binding of ligand to c-met using a c-met antagonist that disrupts c-met multimerization.

1 . A c-met antagonist that disrupts c-met dimerization, wherein binding of the antagonist to c-met inhibits HGF dependent or independent c-met activation. 
     
     
         2 - 21 . (canceled) 
     
     
         22 . A composition comprising the antagonist of  claim 1  and a carrier. 
     
     
         23 . The composition of  claim 22 , wherein the carrier is pharmaceutically acceptable. 
     
     
         24 . A nucleic acid encoding the antagonist of  claim 1 , wherein the antagonist comprises a polypeptide. 
     
     
         25 . The nucleic acid of  claim 24 , wherein the antagonist comprises an antibody or fragment thereof. 
     
     
         26 . A vector comprising the nucleic acid of  claim 24 . 
     
     
         27 . A host cell comprising the vector of  claim 26 . 
     
     
         28 . An article of manufacture comprising: a container; and a composition contained within the container, wherein the composition comprises the antagonist of  claim 1 . 
     
     
         29 . (canceled) 
     
     
         30 . A kit comprising: a first container comprising a composition comprising the antagonist of  claim 1 ; and a second container comprising a buffer. 
     
     
         31 - 38 . (canceled) 
     
     
         39 . A method of inhibiting c-met activated cell proliferation, said method comprising contacting a cell or tissue with the antagonist of  claim 1 , whereby cell proliferation associated with c-met activation is inhibited. 
     
     
         40 . A method of treating a pathological condition associated with dysregulation of c-met activation in a subject, said method comprising to administering to the subject the antagonist of  claim 1 , whereby c-met activation is inhibited. 
     
     
         41 . A method of inhibiting the growth of a cell that expresses c-met or hepatocyte growth factor, or both, said method comprising contacting said cell with the antagonist of  claim 1  thereby causing an inhibition of growth of said cell. 
     
     
         42 . A method of therapeutically treating a mammal having a cancerous tumor comprising cells that express c-met or hepatocyte growth factor, or both, said method comprising administering to said mammal a therapeutically effective amount of the antagonist of  claim 1 , thereby effectively treating said mammal. 
     
     
         43 . A method for treating or preventing a cell proliferative disorder associated with increased expression or activity of c-met or hepatocyte growth, or both, said method comprising administering to a subject in need of such treatment an effective amount of the antagonist of  claim 1 , thereby effectively treating or preventing said cell proliferative disorder. 
     
     
         44 . The method of  claim 43 , wherein said proliferative disorder is cancer. 
     
     
         45 . A method for inhibiting the growth of a cell, wherein growth of said cell is at least in part dependent upon a growth potentiating effect of c-met or hepatocyte growth factor, or both, said method comprising contacting said cell with the antagonist of  claim 1 , thereby inhibiting the growth of said cell. 
     
     
         46 . A method of therapeutically treating a tumor in a mammal, wherein the growth of said tumor is at least in part dependent upon a growth potentiating effect of c-met or hepatocyte growth factor, or both, said method comprising contacting said cell with the antagonist of  claim 1 , thereby effectively treating said tumor. 
     
     
         47 . The method of  claim 46 , wherein said cell is a cancer cell. 
     
     
         48 . The method of  claim 47 , wherein said cancer cell is further exposed to radiation treatment or a chemotherapeutic agent. 
     
     
         49 . The method of  claim 47 , wherein said cancer cell is selected from the group consisting of a breast cancer cell, a colorectal cancer cell, a lung cancer cell, a papillary carcinoma cell, a prostate cancer cell, a lymphoma cell, a colon cancer cell, a pancreatic cancer cell, an ovarian cancer cell, a cervical cancer cell, a central nervous system cancer cell, an osteogenic sarcoma cell, a renal carcinoma cell, a hepatocellular carcinoma cell, a bladder cancer cell, a gastric carcinoma cell, a head and neck squamous carcinoma cell, a melanoma cell and a leukemia cell. 
     
     
         50 . The method of  claim 47 , wherein c-met or hepatoctye growth factor, or both, is more abundantly expressed by said cancer cell as compared to a normal cell of the same tissue origin. 
     
     
         51 - 53 . (canceled) 
     
     
         54 . The method of  claim 42  wherein in the absence of said antagonist c-met activation occurs independent of ligand. 
     
     
         55 . The method of  claim 42  wherein in the absence of said antagonist c-met activation is ligand dependent.